Baran, Richter Essentials of Heterocyclic Chemistry-I Heterocyclic Chemistry

5 4 Deprotonation of N–H, Deprotonation of C–H, Deprotonation of Conjugate Acid 3 4 3 4 5 4 3 5 6 6 3 3 4 6 2 2 N 4 4 3 4 3 4 3 3 5 5 2 3 5 4 N HN 5 2 N N 7 2 7 N N 5 2 5 2 7 2 2 1 1 N NH H H 8 1 8 N 6 4 N 5 1 2 6 3 4 N 1 6 3 1 8 N 2-Pyrazoline Pyrazolidine H N 9 1 1 5 N 1 Quinazoline N 7 7 H Cinnoline 1 Pyrrolidine H 2 5 2 5 4 5 4 4 Isoindole 3H-Indole 6 Pyrazole N 3 4 Pyrimidine N pK : 11.3,44 Carbazole N 1 6 6 3 N 3 5 1 a N N 3 5 H 4 7 H pKa: 19.8, 35.9 N N pKa: 1.3 pKa: 19.9 8 3 Pyrrole 1 5 7 2 7 N 2 3 4 3 4 3 4 7 Indole 2 N 6 2 6 2 N N pK : 23.0, 39.5 2 8 1 8 1 N N a 6 pKa: 21.0, 38.1 1 1 2 5 2 5 2 5 6 N N 1 4 Pteridine 4 4 7 Phthalazine 1,2,4-Triazine 1,3,5-Triazine N 1 N 1 N 1 5 3 H N H H 3 5 pK : <0 pK : <0 3 5 Indoline H a a 3-Pyrroline 2H-Pyrrole 2-Pyrroline Indolizine 4 5 4 4 pKa: 4.9 2 6 N N 4 5 6 3 N 6 N 3 5 6 3 N 5 2 N 1 3 7 2 1 4 4 3 4 3 4 3 4 3 3 N 4 4 2 6 5 5 5 Pyrazine 7 2 6 Pyridazine 2 3 5 3 5 N 2 8 N 1 2 2 1 8 N 2 5 O 2 5 pKa: 0.6 H 1 1 N10 9 7 H pKa: 2.3 O 6 6 2 6 2 6 6 S Piperazine 1 O 1 O S 1 1 Quinoxaline 1H-Indazole 7 7 1 1 O1 7 Phenazine Furan Thiophene Benzofuran Isobenzofuran 2H-Pyran 4H-Pyran Benzo[b]thiophene Effects of Substitution on Pyridine Basicity: pKa: 35.6 pKa: 33.0 pKa: 33.2 pKa: 32.4 t 4 Me Bu NH2 NHAc OMe SMe Cl Ph vinyl CN NO2 CH(OH)2 4 8 5 4 9 1 3 2-position 6.0 5.8 6.9 4.1 3.3 3.6 0.7 4.5 4.8 –0.3 –2.6 3.8 6 3 3 5 7 4 8 2 3 5 2 3-position 5.7 5.9 6.1 4.5 4.9 4.4 2.8 4.8 4.8 1.4 0.6 3.8 4 2 6 7 7 3 N2 N 1 4-position 6.0 6.0 9.2 5.9 6.6 6.0 3.8 5.5 5.5 1.9 1.6 4.7 2 N N 5 4 N 1 1 6 5 8 3 5 H 6 4 1 6 3 Quinuclidine Isoquinoline Lithiation Positions: First, Second R 2 6 Piperidine 4H-Quinolizine N pK : 11.0 pK : 5.4 7 2 N N N 1 pKa: 11.2 a 5 4 a N 1 9 8 6 3 5 4 8 1 Pyridine N R 2 7 6 3 Quinoline N S O O S S S N S pKa: 5.2 7 2 Me R 3 6 N 7 2 pKa: 4.92 thermodynamic N 8 H 1 N N N 4 10 5 8 1 N Acridine Tetrahydroquinoline 1,8-Naphthyridine pK : 5.0 pK : 5.6 a pK : 3.39 S N kinetic O a a S Me N N 4 3 4 3 3 3 4 3 4 4 3 4 N 5 N 5 N N Sites of Electrophilic Substitution: Major, Minor 2 2 2 2 2 5 N 5 N 5 2 5 N 6 6 S S O 1 O O 1 S 1 1 1 1 7 7 N Oxazole Isothiazole Thiazole S N O N Isoxazole Benzoxazole Benzthiazole H N H N H pKa: –0.5 pKa: 2.5, 29.4 pKa: 0.8 pKa: –3 pKa: 24.4 pKa: 27.0 N N 3 4 3 4 N 4 3 3 4 N N N N N 5 S N O S N 2 5 2 2 N 5 H 2 5 N H S 1 6 3 4 N N 1 N 1 N 1 7 H H H 3 1,3,4-Thiadiazole 9 Lipinski Rule of Five: Heterocyclic Aromaticity Values: 2 5 1,2,3-Triazole 4 2-Imidazoline Benzimidazole 2 N N pKa: –4.9 Christopher Lipinski (retired from Pfizer) formulated a set of % (of PhH) β-value % (of PhH) β-value N 1 pKa: 9.3 8 H pKa: 16.4 criteria fulfilled in most orally available drugs. 1 N pyridine 82 0.058 indole 0.047 Imidazole 3 3 4 3 4 5 N 7 1. No more than five hydrogen bond donors. tetrazole 80 benzothiophene 0.044 HN 4 N N 3 N 6 H pK : 6.9, 14.4, 33.7 4 2. No more than ten hydrogen bond acceptors. pyrazole 61 imidazole 43 0.042 a 2 N 5 N 2 2 5 2 N 5 Purine 3. A molecular weight under 500. quinoline 61 0.052 pyrrole 37 0.039 N 1 N 5 N N 1 H 1 pKa: 2.5, 8.9 4. A LogP (partition coefficient) value under five. isoquinoline 0.051 benzofuran 0.036 H O 1 H Imidazolidine Tetrazole 1,2,4-Triazole pyrazine 75 0.049 thiophene 45 0.032 pK : 4.9 1,2,3-Oxadiazole Medicinal Chemistry Glossary: 1,2,5-triazole 71 isoindole 0.029 a pKa: 2.2, 10.3, 26.2 ED50: Dose required to yield maximum therapeutic effect in 50% pyrimidine 67 0.049 furan 12 0.007 of test animals. pyridazine 65 isobenzofuran 0.002 4 5 6 4 4 S 3 5 S Efficacy: Description of the relative intensity with which agonists 3 7 S S 3 5 vary in the response they produce, even with similar affinity. 2 6 2 8 2 6 H 4 Homologue: A compound belonging to a series of compounds differing from each other by a repeating unit (i.e. a CH2, a peptide residue, etc.). 4 N S S 1 10 9 4 1 1 N Intrinsic activity: The maximal stimulatory response induced by a compound relative to that of a given reference comopund. O H 3 5 3 5 Phenothiazine 3 S 5 1,3,5-Trithiane 1,4-Dithiane LD50: Dose required to kill 50% of test animals. 2 6 2 6 Partition coefficient (LogP): Log10 of the ratio of a compound's concentration in 1-octanol vs. water at equilibrium. A LogP<0 means that 2 6 O O H 4 4 5 6 1 1 3 4 S O a compound is more soluble in water than in 1-octanol. O N 1 3 7 1,4-Dioxane 3 5 Morpholine Pharmacophore: The ensemble of steric and electronic features that is necessary to ensure the optimal supramolecular interactions with a 2 5 1,3-Dithiane 2 8 pK : 8.4 specific biological target structure and to trigger (or block) its biological response. This is not a real molecule or moiety, but rather an O 2 6 a 1 S pKa: 31 N abstract concept that is considered the largest common denominator shared by a set of active molecules. 1 1 H 10 9 1,3-Dioxolane Thiomorpholine Phenoxazine Potency: The dose of a drug required to produce a specific effect of given intensity as compared to a standard reference. Therapeutic index: LD50/ED50 Baran, Richter Essentials of Heterocyclic Chemistry-I Heterocyclic Chemistry

Indoles: R' R' R' Pyrroles: R' X X R O COY O 0 II R' O R' Pd Pd NO R' R' 2 CN CO2X + NH R R Y X 2 R N CO2X N N N R' base R NH H acid, Δ N R R R N 2 R N H H O X H Fischer Indole Synthesis Knorr Pyrrole Synthesis i. tBuOCl Barton-Zard Pyrrole Synthesis ii. Me R' - O Me S O CO2Me nBu SnH O RNH R S 3 R' R 2 NHR DMAD R' N R iii. base N X CO2Me R' AIBN R N+ N O R N R N iv. Raney-Ni, H H H 2 Ph Ph Fukuyama Indole Synthesis Gassman Indole Synthesis Paal-Knorr Pyrrole Synthesis Huisgen Pyrrole Synthesis R'' I R' R'' OMe PdII; MeO CO Me Me 2 RNH Zn Pd(OAc)2, R' 2 N CO2Me NH2 [H] NHR base N N HOAc H N MeO C N R PdII R 2 MeO C N Hegedus Indole Synthesis Larock Indole Synthesis 2 H Boger Pyrrole Synthesis R2 Me R O R2 2 NO2 R2 Me Me i. DMFDMA Me H2NNH2 + + R R 1 R Et R R1 N ii. Pd/C, H N Me CoI , H2N R1 R BrMg R1 NO 2 2 Δ N N H 2 H O Et H Br R H R Piloty Pyrrole Synthesis Hantzsch Pyrrole Synthesis Bartoli Indole Synthesis Batcho-Leimgruber Indole Synthesis

X N Thiophenes: i. PhNHNH2 R HN N Δ OH NaHSO , 3 Δ N O i. DMAD, R R piperidine P S Me HS CO2Me ii. H+ R N Me 4 10 CO2Me H Me X = OH, NH Me S ii. NaOMe S 2 O MeO2C Fiesselmann Thiophene Synthesis Bucherer Carbazole Synthesis Graebe-Ullmann Carbazole Synthesis Paal Thiophene Synthesis

R3 Ph X R3 R O i. NaOEt, 2 Ph i. S R O R2 HO S(CH2CO2Et)2 R1 O CN 8 1 O Base Ph R R R + Ph CO2H + NH2 2 R1 ii. acid ii. Amine Δ N R HN R O S X S N R2 O 3 1 N HO2C R2 R2 R R1 R R R 1 3 Hinsberg Thiophene Synthesis Gewald Aminothiophene Synthesis Madelung Indole Synthesis Nenitzescu Indole Synthesis Oxazoles and Isoxazoles: i. (CO2Et)2, CN Base i. LA CHO TosMIC O + R' R R CO2H OH R'CHO O Ph + Cl NO ii. [H], H N NH ii. NaBH4 N R K2CO3 N 2 H 2 H R CN HCl N van Leusen Oxazole Synthesis Reissert Indole Synthesis Sugasawa Indole Synthesis Fisher Oxazole Synthesis

O Ar R O OH O R' O R' H+ R NH OH + Ar I R'' R'' CO2X 2 R N N R N CuOTf R H X Δ N R' O NH2 O R' R X = halide H NH2 N H Robinson-Gabriel Oxazole Synthesis Claisen Isoxazole Synthesis Bischler Indole Synthesis Castro Indole Synthesis

Me R O R O Cl CO R + 0 2 H Ni R1 Δ R2 HN CO H N N 2 Ac2O N CO2R O N 3 Δ N N N R O O H R R R2 R1 R O O Hemetsberger Indole Synthesis Mori-Ban Indole Synthesis Cornforth Rearrangement Erlenmeyer-Plöchl Azlactone Synthesis